title: Pak and Rac GTPases promote oncogenic KIT-induced neoplasms.
abstract: An acquired somatic mutation at codon 816 in the KIT receptor tyrosine kinase is associated with poor prognosis in patients with systemic mastocytosis and acute myeloid leukemia (AML). Treatment of leukemic cells bearing this mutation with an allosteric inhibitor of p21-activated kinase (Pak) or its genetic inactivation results in growth repression due to enhanced apoptosis. Inhibition of the upstream effector Rac abrogates the oncogene-induced growth and activity of Pak. Although both Rac1 and Rac2 are constitutively activated via the guanine nucleotide exchange factor (GEF) Vav1, loss of Rac1 or Rac2 alone moderately corrected the growth of KIT-bearing leukemic cells, whereas the combined loss resulted in 75% growth repression. In vivo, the inhibition of Vav or Rac or Pak delayed the onset of myeloproliferative neoplasms (MPNs) and corrected the associated pathology in mice. To assess the role of Rac GEFs in oncogene-induced transformation, we used an inhibitor of Rac, EHop-016, which specifically targets Vav1 and found that EHop-016 was a potent inhibitor of human and murine leukemic cell growth. These studies identify Pak and Rac GTPases, including Vav1, as potential therapeutic targets in MPN and AML involving an oncogenic form of KIT.
authors.forename: Holly
authors.initials: H
authors.lastname: Martin
authors.forename: Raghuveer Singh
authors.initials: RS
authors.lastname: Mali
authors.forename: Peilin
authors.initials: P
authors.lastname: Ma
authors.forename: Anindya
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Baskar
authors.initials: B
authors.lastname: Ramdas
authors.forename: Emily
authors.initials: E
authors.lastname: Sims
authors.forename: Veerendra
authors.initials: V
authors.lastname: Munugalavadla
authors.forename: Joydeep
authors.initials: J
authors.lastname: Ghosh
authors.forename: Ray R
authors.initials: RR
authors.lastname: Mattingly
authors.forename: Valeria
authors.initials: V
authors.lastname: Visconte
authors.forename: Ramon V
authors.initials: RV
authors.lastname: Tiu
authors.forename: Cornelis P
authors.initials: CP
authors.lastname: Vlaar
authors.forename: Suranganie
authors.initials: S
authors.lastname: Dharmawardhane
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D063646:Carcinogenesis / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004789:Enzyme Activation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008415:Mastocytosis / Q000188:drug therapy; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D002227:Carbazoles; C572775:N4-(9-ethyl-9H-carbazol-3-yl)-N2-(3-morpholin-4-ylpropyl)-pyrimidine-2,4-diamine; C487513:NSC 23766; D051567:Proto-Oncogene Proteins c-vav; D011743:Pyrimidines; C496618:VAV1 protein, human; D019009:Proto-Oncogene Proteins c-kit; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins